Purpose: Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr. Methods: Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation. Results: One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85–130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min. Conclusions: This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.

Purpose The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment. Methods This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson’s correlation coefficient. Results Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5–63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups. Conclusion This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.

Purpose: Some patients do not respond to initial therapy for exacerbation of chronic obstructive pulmonary disease (ECOPD), resulting in treatment failure that requires antimicrobial changes or advanced therapies. Appropriate treatment is possible if patients at a high risk of treatment failure at the start of treatment are properly identified. Therefore, this study examined the factors associated with initial treatment failure in patients with ECOPD. Patients and Methods: We conducted a cohort study involving patients with ECOPD admitted to our hospital. The primary outcome was initial treatment failure, defined as a composite of treatment intensification for ECOPD and in-hospital mortality. Uni- and multivariate analyses were performed to identify the factors associated with initial treatment failure. Results: The analysis included data of 152 patients with a mean age of 76± 8 years (mean±standard deviation); 81% of them were male patients. Treatment failure occurred in 26 (17%) patients. These included nine, two, one, and 14 patients who changed antimicrobial agents, received additional non-invasive positive pressure ventilation therapy due to non-improvement or symptom exacerbation, received additional invasive positive pressure ventilation therapy, and died in the hospital, respectively. Using multivariable analysis, home oxygen therapy (odds ratio, 5.335; 95% confidence interval, [1.542– 18.457]), neutrophil count ≥ 7000 cells/μL (3.550; [1.007– 12.519]), and acidemia (3.129; [1.009– 9.698]) were significant factors associated with treatment failure. In patients treated with narrow-spectrum antibiotics as the initial antibacterial therapy, the treatment failure rate in patients receiving home oxygen therapy was significantly higher than in those receiving none. Conclusion: Home oxygen therapy, high neutrophil count, and acidemia on admission were risk factors for treatment failure. Particularly, patients receiving home oxygen therapy were at a higher risk of treatment failure with the use of narrow-spectrum antibiotics.

Background/Objectives: Augmented renal clearance (ARC) may reduce blood concentrations of renally eliminated antibiotics and increase the risk of treatment failure in sepsis. We investigated the risk factors for ARC and the effect of inflammation on ARC duration. Methods: This retrospective cohort study included 282 patients treated for sepsis. The primary endpoint was the ARC incidence, while the secondary endpoints were the relationship between the ARC duration and the time courses of inflammatory marker levels. Patient characteristics, disease severity, laboratory data, and treatment data were collected from medical records. Risk factors for ARC were identified using logistic regression. The effect of the inflammatory response on the ARC duration was evaluated using the Mann–Whitney U test. Results: Among 174 patients (median age, 78 years [range: 29–95]; 94 [54.0%] male; the median intensive care unit length of stay was 6 days [1–76 days]) with ARC identified in 15.5% of patients. Significant risk factors for ARC were age < 75 years (odds ratio, 4.748), albumin levels < 3.0 g/dL (3.672), serum potassium levels < 3.6 mmol/L (5.196), and sequential organ failure assessment scores ≤ 9 (3.803). Patients with an ARC duration of ≥ 8 days had significantly higher white blood cell counts and C-reactive protein levels at ARC incidence than those with an ARC duration < 8 days. Conclusions: Age, albumin, serum potassium, and sequential organ failure assessment scores were risk factors for ARC in patients with sepsis. Persistent inflammation may prolong ARC. These findings can aid in choosing antibiotic dosing regimens based on renal function in patients with sepsis at high risk of ARC.

Sunitinib is associated with a high incidence of hand-foot skin reaction (HFSR) that significantly affects the quality of life and treatment continuation of the patient. The relationships between the concentrations of sunitinib and its metabolites in tissues and the occurrence of HFSR are crucial to preventing it. Therefore, this study developed a quantitative method for measuring the concentrations of sunitinib and its metabolites in human nails and skin. In addition, we evaluated whether this method can be applied to measure these drug concentrations in clinical samples. Nails or skin were crushed, methanol was added, and the supernatant obtained by centrifugation was used for analysis. Sunitinib, its metabolites, and voriconazole (internal standard: IS) were analyzed using liquid chromatography/mass spectrometry with electrospray ionization in positive mode. All samples were processed in the dark, and the analysis time was 5 min/run. In nail samples, calibration curves were linear in the range of 40-2000 pg/mg for sunitinib and N-desethyl sunitinib and 4-200 pg/mg for sunitinib N-oxide. In skin samples, linearity was observed in the range of 400-6000 pg/mg for sunitinib and N-desethyl sunitinib and 8-120 pg/mg for sunitinib N-oxide. The intra- and inter-day precision and accuracy were within 15 %, with a lower limit of quantification of 20 %. Extraction recoveries were ≥ 80 %, and the coefficients of variation for the IS-normalized matrix coefficients were < 15 %. This method was successfully applied to quantify these compounds in the nails and skin of patients receiving sunitinib treatment.